Biaromatic propynyl compounds, pharmaceutical and cosmetic compositions containing same, and uses thereof

ABSTRACT

Compounds of general formula (I) are described. Also described, is the use of such compounds in pharmaceutical compositions for use in human or veterinary medicine (dermatological, rheumatic, respiratory, cardiovascular and ophthalmologic disorders, in particular), or in cosmetic compositions.

CROSS-REFERENCE TO PRIOR APPLICATIONS

This application is the U.S. National Stage of PCT/IB2017/000075, filedFeb. 3, 2017, (published in the French language on Aug. 10, 2017 as WO2017/134513 A1; the title and abstract were also published in English),which claims priority under 35 U.S.C. § 119 of U.S. ProvisionalApplication No. 62/290,707, filed Feb. 3, 2016, each hereby expresslyincorporated by reference in its entirety and each assigned to theassignee hereof.

The invention relates to bi-aromatic compounds as novel and usefulindustrial products. It also relates to the use of these novel compoundsin pharmaceutical compositions intended for use in human or veterinarymedicine, or in cosmetic compositions.

The compounds according to the invention have marked activity in thedomains of cellular differentiation and proliferation, and findapplications more particularly in the topical and systemic treatment ofdermatological conditions related to a keratinization disorder,dermatological (or other) conditions with an inflammatory and/orimmunoallergic component, and dermal or epidermal proliferations,whether benign or malignant. These compounds may also be used in thetreatment of connective-tissue degeneration disorders, to combat skinaging, whether photo-induced or chronological, and to treat healingdisorders. They can also be applied in the ophthalmological field,especially in the treatment of corneal diseases.

The compounds according to the invention can also be used in cosmeticcompositions for body and hair hygiene.

The compounds according to the invention can be represented by generalformula (I) below:

in which:

-   -   Ar represents a radical chosen from among the radicals of        formulas (a) or (b) below:

-   -   -   R₅ having the meaning given below,

    -   R₁ represents: (i) a hydrogen atom        -   (ii) a —CH₃ radical        -   (ii) a —CH₂—O—R₆ radical        -   (iv) an —O—R₆ radical        -   (v) a —CO—R₇ radical,        -   (vi) an —S(O)_(t)R₉ radical

R₆, R₇, R₉ and t having the meaning given below,

-   -   R₂ and R₃ represent a hydrogen atom, a linear or branched alkyl        radical having 1 to 20 carbon atoms, an —OR₆ radical or an —SR₆        radical, R₆ having the meaning given below, given that R₂ and        R₃, taken together, can form with the adjacent aromatic ring a        5- or 6-member ring optionally substituted by methyl groups        and/or optionally interrupted by an oxygen or sulfur atom,    -   R₄ represents a hydrogen atom, a halogen atom, a lower alkyl        radical or an —OR₆ radical, R₆ having the meaning given below,

given that in all of the preceding:

-   -   R₆ represents a hydrogen atom, a lower alkyl radical, a linear        or branched alkyl radical having 1 to 20 carbon atoms, an        —O—CH₃—R₉ radical or a —CO—R₉ radical, R₉ having the meaning        given below,    -   R₇ represents:        -   (a) a hydrogen atom        -   (b) a lower alkyl radical        -   (c) a radical of formula:

-   -   R′ and R″ having the meaning given below,        -   (d) an —OR₈ radical, R₈ having the meaning given below,    -   R₈ represents a hydrogen atom, methyl, ethyl, propyl,        cyclopropyl, cyclobutyl, or cyclopentyl, an alkenyl radical, a        mono- or polyhydroxyalkyl radical, an optionally substituted        aryl or aralkyl radical or a sugar residue or an amino acid or        peptide residue,    -   R₉ represents a lower alkyl or methyl, ethyl, propyl,        cyclopropyl, cyclobutyl, cyclopentyl radical,    -   R′ and R″ represent a hydrogen atom, a lower alkyl radical, a        mono- or polyhydroxyalkyl radical, an optionally substituted        aryl radical or an amino acid or peptide or sugar residue, or        even, taken together, form a heterocycle,    -   t is a whole number equal to 0, 1 or 2.

The invention also pertains to salts of compounds of formula (I) abovein the case where R₁ represents a carboxylic acid function, as well asthe optical and geometric isomers of said compounds. When compoundsaccording to the invention are present in the form of salts, they arepreferably alkali metal or alkaline-earth metal salts, or even zinc oran organic amine compound.

According to the present invention, lower alkyl radical means a radicalhaving 1 to 6 carbon atoms, preferably methyl, ethyl, isopropyl, butyl,tert-butyl and hexyl radicals.

Linear or branched alkyl radical having 1 to 20 carbon atoms means, inparticular, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl,2-ethylhexyl, octyl, dodecyl, hexadecyl, and octadecyl radicals.

Monohydroxyalkyl radical means a radical preferably having 2 or 3 carbonatoms, notably a 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropylradical.

Polyhydroxyalkyl radical means a radical preferably containing 3 to 6carbon atoms and 2 to 5 hydroxyl groups such as 2,3-dihydroxypropyl,2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl radicals orpentaerythritol residue.

Aryl radical means, preferably, a phenyl radical optionally substitutedwith at least one halogen atom, a hydroxyl, or a nitro function.

Aralkyl radical means, preferably, the benzyl or phenethyl radicaloptionally substituted with at least one halogen atom, hydroxyl, or anitro function.

Alkenyl radical means a radical containing preferably 1 to 5 carbonatoms and having one or more ethylene unsaturations, such as, moreparticularly, the allyl radical.

Sugar residue means a residue particularly deriving from glucose,galactose or mannose, or even glucuronic acid.

Amino acid residue particularly means a residue deriving from lysine,glycine or aspartic acid, and peptide residue means, more particularly,a dipeptide or tripeptide residue resulting from the combination ofamino acids.

Finally, heterocycle particularly means, preferably, a piperidino,morpholino, pyrrolidino or piperazino radical, possibly substituted inposition 4 by a C₁-C₆ alkyl radical or mono- or polyhydroxyalkyl such asdefined above.

When R₄ and R₅ represent a halogen atom, this is preferably a fluorine,chlorine or bromine atom.

The compounds of general formula (I) above within the scope of thepresent invention notably include the following compounds:

According to the present invention, the compounds of formula (I) moreparticularly preferred are those for which R₅ represents —OH, R₇represents an OR₈ radical, and R₁₁ represents an —OR₆ radical, R₆ andR₁₁ having the meaning given above.

The compounds according to the invention are particularly well suited inthe following treatment fields:

-   -   1) to treat dermatological conditions linked to a keratinization        disorder pertaining to cellular differentiation and        proliferation, especially to treat acne vulgaris, comedonic or        polymorphic acne, rosacea, nodulocystic acne, acne conglobata,        senile acne, and secondary acnes such as solar, drug-induced or        occupational acne;    -   2) to treat keratinization disorders, especially ichthyosis,        ichthyosiform states, Darier's disease, palmoplantar        keratoderma, leukoplakia and leukoplakiform conditions,        cutaneous or mucosal (buccal) lichen;    -   3) to treat other dermatological conditions associated with a        keratinization disorder with an inflammatory and/or        immunoallergic component and, in particular, all forms of        psoriasis whether cutaneous, mucosal or nail, and psoriatic        arthritis, or cutaneous atopy, such as eczema or respiratory        atopy or gingival hypertrophy; the compounds may also be used in        certain inflammatory conditions which do not present a        keratinization disorder,    -   (4) to treat dermal or epidermal proliferations, whether benign        or malignant, whether of viral origin or not such as common        warts, flat warts and verruciform epidermodysplasia, oral or        florid papillomatoses and proliferations that can be induced by        UV radiation, in particular basal and prickle cell epithelioma,    -   5) to treat other dermatological disorders such as bullous        dermatosis and collagen diseases,    -   6) to treat certain ophthalmological problems, especially        corneal diseases,    -   7) to repair or combat aging of the skin, whether photo-induced        or chronological or to reduce pigmentation and actinic        keratosis, or any pathologies associated with chronological or        actinic aging,    -   8) to prevent or treat stigmata of epidermal and/or dermal        atrophy induced by local or systemic corticosteroids, or any        other form of cutaneous atrophy,    -   9) to prevent or treat healing disorders or to prevent or repair        stretch marks,    -   10) to combat disorders of sebaceous function, such as        hyperseborrhea associated with acne or simple seborrhea,    -   11) in the treatment or prevention of cancerous or precancerous        conditions,    -   12) in the treatment of inflammatory disorders such as        arthritis,    -   13) in the treatment of any skin or general condition of viral        origin,    -   14) in the prevention or treatment of alopecia,    -   15) in the treatment of dermatological or general conditions        with an immunological component,    -   16) in the treatment of cardiovascular system disorders such as        atherosclerosis.

In the abovementioned therapeutic fields, the compounds according to theinvention can advantageously be used in combination with other compoundswith retinoid activity, with D vitamins or derivatives thereof, withcorticosteroids, with anti-free radicals, α-hydroxy or α-keto acids orderivatives thereof, or with ion channel blockers. D vitamins orderivatives thereof means, for example, vitamin D₂ or D₃ derivatives andin particular 1,25-dihydroxyvitamin D₃. Anti-free radicals means, forexample, α-tocopherol, superoxide dismutate, ubiquinol or certain metalchelators. α-hydroxy or α-keto acids or derivatives thereof means, forexample, lactic, malic, citric, glycolic, mandelic, tartaric, glycericor ascorbic acids or salts thereof, amides or esters. Finally, ionchannel blockers means, for example, minoxidil(2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives.

The present invention also has for a subject medicinal compositionscontaining at least one compound of formula (I) such as defined above,one of its optical or geometric isomers or one of its salts.

The present invention therefore also has for a subject a novel medicinalcomposition intended in particular for treatment of the abovementionedconditions, which is characterized by the fact that it comprises, in apharmaceutically-acceptable carrier and compatible with the selectedmode of administration thereof, at least one compound of formula (I),one of the optical isomers thereof or one of the salts thereof.

The composition according to the invention can be administeredenterally, parenterally, topically or ocularly.

For enteral administration, the composition may be in the form oftablets, hard capsules, dragées, syrups, suspensions, solutions,powders, granulates, emulsions, microspheres or nanospheres or lipid orpolymer vesicles permitting controlled release. For parenteraladministration, the compositions can advantageously be in the form ofsolutions or suspensions for infusion or for injection.

The compounds according to the invention are generally administered at adaily dosage of approximately 0.01 mg/kg to 100 mg/kg of bodyweight, in1 to 3 doses.

For topical administration, the pharmaceutical compositions based oncompounds according to the invention are more particularly intended fortreatment of the skin and mucosa and may then be in the form ofointments, creams, milks, pomades, powders, swabs, solutions, gels,sprays, lotions or suspensions. They may also be in the form ofmicrospheres or nanospheres or lipid or polymer vesicles, or polymerpatches and hydrogels permitting controlled release. These topicalcompositions may also be in the anhydrous or the aqueous form, dependingon the clinical indication.

For ocular administration, they are mainly eye drops.

These compositions for topical or ocular use contain at least onecompound of formula (I) such as defined above, or one of the optical orgeometric isomers thereof or one of the salts thereof, at aconcentration preferably comprised between 0.001% and 5% by weightrelative to the total weight of the composition.

Compounds of formula (I) according to the invention also findapplication in the cosmetic field, in particular in body and hairhygiene and especially for the treatment of acne-prone skin, for hairregrowth and loss prevention, to treat oily skin or hair, to protectagainst the harmful aspects of the sun or in the treatment ofphysiologically dry skin, to prevent and/or to combat photo-induced orchronological aging.

In the cosmetic field, the compounds according to the invention canfurther advantageously be used in combination with other compounds withretinoid activity, with D vitamins or derivatives thereof, withcorticosteroids, with anti-free radicals, α-hydroxy or α-keto acids orderivatives thereof, or with ion channel blockers, all these variousproducts being as defined above.

The present invention therefore also relates to a cosmetic compositionwhich is characterized by the fact that it comprises, in acosmetically-acceptable carrier and suitable for topical application, atleast one compound of formula (I) as defined above or one of the opticalor geometric isomers thereof or one of the salts thereof; this cosmeticcomposition may be in the form of a cream, a milk, a lotion, a gel,microspheres or nanospheres or lipid or polymer vesicles, a soap or ashampoo.

The concentration in compound of formula (I) in cosmetic compositionsaccording to the invention is advantageously comprised between 0.001%and 3% by weight relative to the whole composition.

The medicinal and cosmetic compositions according to the invention mayalso contain inert additives or even pharmacodynamically orcosmetically-active additives, or combinations of these additives, andin particular: wetting agents; depigmenting agents such as hydroquinone,azelaic acid, caffeic acid or kojic acid; emollients; hydrating agentssuch as glycerol, PEG 400, thiamorpholinone, and derivatives thereof orurea; anti-seborrheic or anti-acne agents, such asS-carboxymethylcysteine, S-benzyl-cysteamine, salts or derivativesthereof, or benzoyl peroxide; antibiotics such as erythromycin andesters thereof, neomycin, clindamycin and esters thereof, tetracyclines;antifungal agents such as ketoconazole orpolymethylene-4,5-isothiazolidones-3; agents promoting regrowth of hairsuch as minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) andderivatives thereof, diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine1,1-dioxide) and phenytoin (5,4-diphenyl-imidazolidine 2,4-dione);non-steroidal anti-inflammatory agents; carotenoids and, in particular,β-carotene; anti-psoriatic agents such as anthralin and derivativesthereof; and finally eicosa-5,8,11,14-tetraynoic andeicosa-5,8,11-trynoic acids, esters and amides thereof.

The compositions according to the invention may also contain flavors,preservatives such as para-hydroxybenzoic acid esters, stabilizers,moisture regulators, pH regulators, osmotic pressure modifiers,emulsifiers, UV-A and UV-B filters, antioxidants such as α-tocopherol,butylhydroxyanisole or butylhydroxytoluene.

We will now give several examples, for illustration purposes andnon-limiting, to validate the activity of active compounds of formula(I) according to the invention, as well as various concrete formulationsbased on such compounds.

EXAMPLE 1: TRANSACTIVATION TEST

a) Test Principle:

Activation of receptors by an agonist (activator) in HeLa cells leads tothe expression of a reporter gene, luciferase, which generates light inthe presence of a substrate. Therefore the activation of receptors canbe measured by quantifying the luminescence produced after incubation ofthe cells in the presence of a reference antagonist. The activatorproducts displace the antagonist from its site, thus permitting thereceptor to be activated. The activity is measured by quantifying theincrease in light produced. This measurement determines the activatingactivity of the useful compound in the invention.

In this study, a constant is determined that represents the affinity ofthe molecule for the receptor. This value can fluctuate according to thebasal activity and expression of the receptor; it is designated apparentKd (KdApp).

To determine this constant, cross curves are created of the product tobe tested(4′-(3-hydroxy-propyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-biphenyl-4-carboxylicacid and4′-(2,3-dihydroxy-propyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphtalen-2-yl)-biphenyl-4-carboxylic)acid versus a reference antagonist also called reference ligand,4-(5,5-dimethyl-8-p-tolyl-5,6-dihydro-naphthalen-2-ylethynyl)-benzocacid. The product to be tested is used at 10 concentrations and thereference antagonist at 7 concentrations. In each well (of a 96-wellplate), the cells are in contact with one concentration of the productto be tested and one concentration of the reference antagonist.

Full agonist controls, also called 100% controls, (4-[2-(5,5,8,8tetramethyl-5,6,7,8 tetrahydronaphthalene-2-yl)propenyl]-benzoic acid)and inverse agonist controls, also called 0% controls,(4-{(E)-3-[4-(4-tert-butyl-phenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-3-oxo-propenyl}-benzoicacid) are also measured.

These cross curves allow determining the AC50 (concentration at which50% activation of the receptor is observed) of the reference ligand atdifferent concentrations of the product to be tested. These AC50s areused to calculate the Schild regression by plotting a line conforming tothe Schild equation (“Quantitation in receptor pharmacology” Terry P.Kenakin, Receptors and Channels, 2001, 7, 371-385).

In the case of an agonist, the AC50 is calculated by plotting the curveof the product at the concentration of the reference ligand giving 80%activation. The percentage of activation that corresponds to the maximumlevel of activity obtained is also measured.

b) Materials and Method:

The HeLa cell lines used are stable transfectants containing theplasmids ERE-βGlob-Luc-SV-Neo (reporter gene) and RAR (α, β, γ)ER-DBD-puro. These cells are inoculated onto 96-well plates in an amountof 10,000 cells per well in 100 μl DMEM medium with no phenol red andsupplemented with 10% delipidated fetal bovine serum. The plates arethen incubated at 37° C., 7% CO₂ for 4 hours.

The different dilutions of the product to be tested, the referenceligand(4-(5,5-dimethyl-8-p-tolyl-5,6-dihydro-naphthalen-2-ylethynyl)-benzoicacid), the 100% control (100 nM 4-[2-(5,5,8,8 tetramethyl-5,6,7,8tetrahydronaphthalene-2-yl)propenyl]-benzoic acid) and the 0% control(500 nM4-{(E)-3-[4-(4-tert-butyl-phenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-3-oxo-propenyl}-benzoicacid) are added in an amount of 5 μl per well. The plates are thenincubated 18 hours at 37° C., 7% CO₂.

The culture medium is removed by turning over and 100 μl of a 1:1 PBS(phosphate buffer solution)/luciferin mixture is added to each well.After 5 minutes, the plates are read by the luminescence reader.

c) Results:

The apparent Kd constant values are indicated in the table below. Thesevalues are compared to those of the compounds of patent WO 99/10308presenting the best activities

RAR RAR alpha RAR beta gamma Kdapp (nM) Kdapp (nM) Kdapp (nM) Compound 1120 4 4 Compound 2 30 2 4

EXAMPLE 2

In this example, various concrete formulations based on the compoundaccording to the invention are illustrated.

A—Oral Administration

(a) 0.2 g tablet Compound prepared in Example 7 0.001 g Starch 0.114 gDicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc 0.010 gMagnesium stearate 0.005 g (b) Oral suspension in 5-ml ampoules Compoundprepared in Example 3 0.001 g Glycerin 0.500 g 70% sorbitol 0.500 gSodium saccharin 0.010 g Methyl parahydroxybenzoate 0.040 g Flavor qsPurified water qs  5 ml (c) 0.8 g tablet Compound of Example 6 0.500 gPregelatinized starch 0.100 g Microcrystalline cellulose 0.115 g Lactose0.075 g Magnesium stearate 0.010 g (d) Oral suspension in 10-ml ampoulesCompound of Example 2 0.200 g Glycerin 1.000 g 70% sorbitol 1.000 gSodium saccharin 0.010 g Methyl parahydroxybenzoate 0.080 g Flavor qsPurified water qs 10 ml

B—Topical Administration

(a) Ointment Compound of Example 9 0.020 g Isopropyl myristate 81.700 g Liquid Vaseline oil 9.100 g Silica (“Aerosil 200” sold by DEGUSSA) 9.180g (b) Ointment Compound of Example 10 0.300 g Codex white Vaseline   100g (c) Nonionic water-in-oil cream2-hydroxy-4-[3-hydroxy-3-(3-tert-butyl-4- 0.100 ghydroxyphenyl)]-1-propynylbenzoic acid Mixture of emulsive lanolinalcohols, waxes 39.900 g  and oils (anhydrous Eucerin) sold by BDF)Methyl parahydroxybenzoate 0.075 g Propyl parahydroxybenzoate 0.075 gSterile demineralized water: qs   100 g (d) Lotion Compound of Example 80.100 g Polyethylene glycol (PEG 400) 69.900 g  Ethanol (95%) 30.000 g (e) Hydrophobic ointment Compound of Example 7 0.300 g Isopropylmyristate 36.400 g  Silicone oil (“Rhodorsil 47 V 300” sold 36.400 g  byRHONE-POULENC) Beeswax 13.600 g  Silicone oil (“Abil 300.000 cst” sold  100 g by GOLDSCHMIDT) (f) Nonionic oil-in-water cream Compound ofExample 3 1.000 g Cetyl alcohol 4.000 g Glycerol monostearate 2.500 gPEG 50 stearate 2.500 g Shea butter 9.200 g Propylene glycol 2.000 gMethyl parahydroxybenzoate 0.075 g Propyl parahydroxybenzoate 0.075 gSterile demineralized water:   100 g

The invention claimed is:
 1. A compound having the structure of formula(I) below:

in which: Ar is a radical selected from the group of radicals of formula(a) or (b) below:

wherein R₅ is OH; R₁ is: (i) a hydrogen atom, (ii) a —CH₃ radical, (ii)a —CH₂—O—R₆ radical, (iv) an —O—R₆ radical, (v) a —CO—R₇ radical, or(vi) an —S(O)_(t)R₉ radical; R₂ and R₃, together with the carbon atomsto which they are attached, form a 5- or 6-membered ring optionallysubstituted by methyl groups and includes only carbon atoms; R₄ is ahalogen atom or an —OR₆ radical; R₆ is a hydrogen atom, a lower alkylradical, a linear or branched alkyl radical having 1 to 20 carbon atoms,or a —CO—R₉ radical; R₇ is a hydrogen atom, a lower alkyl radical, aradical of formula:

or an —OR₈ radical; R₈ is a hydrogen atom, a linear or branched alkylradical having 1 to 20 carbon atoms, an alkenyl radical, a mono- orpolyhydroxyalkyl radical, an optionally substituted aryl or aralkylradical, a sugar residue, an amino acid, or a peptide residue; R₉represents a lower alkyl radical, or a linear or branched alkyl radicalhaving 1 to 20 carbon atoms; each of R′ and R″ is a hydrogen atom, alower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionallysubstituted aryl radical, an amino acid, a peptide residue, or a sugarresidue; or R′ and R″, together with the nitrogen atom to which they areattached, form a heterocycle; and t is 0, 1 or 2, or a salt, or anoptical or geometric isomer thereof.
 2. The compound according to claim1, wherein the compound is an alkali metal or alkaline earth metal salt,a zinc salt, or an organic amine salt.
 3. The compound according toclaim 1, wherein the lower alkyl radicals are selected from the groupconsisting of methyl, ethyl, isopropyl, butyl, tert-butyl, and hexylradicals.
 4. The compound according to claim 1, wherein the linear orbranched alkyl radicals having 1 to 20 carbon atoms are selected fromthe group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl,and cyclopentyl radicals.
 5. The compound according to claim 1, whereinthe monohydroxyalkyl radicals are selected from the group consisting of2-hydroxyethyl, 2-hydroxypropyl, and 3-hydroxypropyl radicals.
 6. Thecompound according to claim 1, wherein the polyhydroxyalkyl radicals areselected from the group consisting of 2,3-dihydroxypropyl,2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl radicals, and apentaerythritol residue.
 7. The compound according to claim 1, whereinthe aryl radical is a phenyl radical optionally substituted with atleast one halogen atom, hydroxyl, or nitro.
 8. The compound according toclaim 1, wherein the aralkyl radicals are selected from the groupconsisting of benzyl or phenethyl radicals optionally substituted by atleast one halogen atom, hydroxyl, or nitro.
 9. The compound according toclaim 1, wherein the alkenyl radicals are selected from the groupconsisting of radicals containing 2 to 5 carbon atoms and having one ormore double bonds.
 10. The compound according to claim 1, wherein thesugar residues are selected from the group consisting of glucose,galactose, mannose, and glucuronic acid residues.
 11. The compoundaccording to claim 1, wherein the amino acid residues are selected fromthe group consisting of residues deriving from lysine, glycine, andaspartic acid.
 12. The compound according to claim 1, wherein thepeptide residues are selected from the group consisting of dipeptide andtripeptide residues.
 13. The compound according to claim 1, wherein theheterocyclic radicals are selected from the group consisting ofpiperidino, morpholino, pyrrolidino, and piperazino radicals, optionallysubstituted in position 4 by a C1-C6 alkyl or mono- or polyhydroxyalkylradical.
 14. The compound according to claim 1, wherein the halogenatoms are selected from the group consisting of fluorine, chlorine, andbromine.
 15. The compound according to claim 1, wherein the compound isan alkali metal salt, an alkaline earth metal salt, a zinc salt, or anorganic amine salt of compound 1 or 2:


16. The compound according to claim 1, wherein R₄ is an —OR₆ radical, R₁is a —CO—R₇ radical, and R₇ is an —OR₈ radical.
 17. The compoundaccording to claim 1, wherein the compound is added to a medicament. 18.The compound according to claim 9, wherein the alkenyl radical is anallyl radical.
 19. A pharmaceutical or cosmetic composition comprisingan effective amount of the compound of claim 1.